Molluscum Contagiosum Virus (MCV), is the only member of the Molluscipoxvirus genus and only infects humans. MCV typically causes unsightly skin lesions that can stigmatize children and young adults. MCV infections are typical in the immunocompromised where it is an opportunistic infection with lesions spreading throughout the surface of the skin and growing to over 1cm in size. MCV is the third most prevalent viral infection of the skin with approximately 20% of children contracting MCV before the age of 15 and 30% of adults being sero-positive for MCV infections. There are no FDA-approved antiviral treatments, no rapid diagnostics, and no vaccine against MCV. This is due primarily to the lack of a tissue culture system to propagate and systematically study MCV infections. The overarching goal of our proposal is to identify the block in tissue culture cells that inhibits ful MCV replication. This in turn will lead to the construction of a tissue culture cell line for the propagation and study of MCV. The immediate goals of this application are; 1) to determining if a surrogate virus (vaccinia) is capable of conditioning tissue culture cells to allow for a productive MCV infection. 2) Identify cellular kinases that are responsible for the inhibition of MCV replication. The first will assess if there are deficiencies in the MCV genome that are responsible for not overcoming cellular defenses and limited pools of required factors that are present in tissue culture. The second will determine if MCV replication is inhibited by the up-regulation of anti-viral cellular defenses. The results obtained from our studies will provide greater insight into the virus-host interactions required for MCV replication. This will be the bass to strategically create a new tissue culture system to propagate MCV, which will enable us to compare and contrast MCV replication and immune evasion to other poxviruses. In addition, this knowledge will ultimately aid in the discovery of targets for antivirals, vaccines and diagnostics against MCV.